Acute Respiratory Distress Syndrome (ARDS) is a devastating syndrome with high morbidity and mortality with no available targeted medical therapies other than supportive care. It is increasingly recognized that one reason for failure of medical interventions is that ARDS is heterogenous. While focus has been placed on the heterogeneity of underlying insults that lead to ARDS (e.g., direct lung injury from pneumonia, aspiration; or indirect injury from sepsis, trauma) less focus has been placed on underlying characteristics that might predispose patients to lung injury, or to a greater severity of lung injury, in response to various insults. We reported an association between preexisting interstitial lung abnormalities (ILA), ARDS, and mortality in small cohort with sepsis or the systemic inflammatory response syndrome (SIRS). We demonstrated that patients with SIRS or sepsis with ILA on chest computed tomography (CT) at least 7 days prior to ICU admission had increased risk to develop ARDS (odds ratio [OR] 4.2, P<0.0001) and die within 28-days (OR 2.3, P=0.01). ILA are radiologic densities on chest CT scans suggestive of underlying interstitial lung disease (ILD) in those without clinical ILD. Patients with clinical PF often die from an acute exacerbation characterized pathologically by diffuse alveolar damage (the most common pathologic finding in ARDS). These findings suggest that one important subgroup of patients at risk to develop, and die from, ARDS includes patients with occult pulmonary fibrosis (PF). Our overarching hypothesis is that plasma biomarkers, correlated with the presence of pre-existing ILA on non-high resolution chest CT, will permit identification of a subgroup of patients with ARDS who will have worse outcomes that can be targeted for (or selected against) in future novel therapeutics and treatment strategies. This RFA permits access to a large cohort of biospecimens from ARDSnet patients in the NHLBI biorepository that we will analyze for biomarkers selected based on association with ARDS and IPF. These findings will be correlated with clinical outcomes and chest CT images obtained from the participating ARDSnet centers. This proposal fulfills the NHLBI strategic goals by investigating newly discovered pathobiological mechanisms important to onset and progression of ARDS, in identifying factors that account for individual differences in pathobiology and response to treatment and clinical management of ARDS, and in developing and optimizing novel diagnostic (and ultimately therapeutic) strategies to detect, prevent, treat, and cure ARDS. To address our hypothesis, we propose two Specific Aims: Aim 1: To identify the frequency of pre-existing ILA in ARDSnet patients and to determine if ILA defines an ARDS subpopulation with an increased rate of mortality. Aim 2: To determine whether a plasma biomarker signature can be identified that predicts worsened outcomes from ARDS in those patients with pre-existing ILA and in ARDS patients overall.